The proposed research is based on the hypothesis that autacoids such as platelet activating factor and eicosanoids are important mediators and modulators of glomerular immune injury. We believe that the autocrine and paracrine actions of these autacoids alters glomerular mesangial function both in vitro ad in vivo and, hence, plays an important role int he development of glomerular immune injury. We will evaluate the roles of platelet activating factor and eicosanoids (leukotrienes, thromboxane and prostaglandins) in three models of experimental glomerular disease. These models are: nephrotoxic serum nephritis, immune complex nephropathy induced by cationic bovine gamma globulin, and murine systemic lupus erythematosus. In these models, we will assess glomerular synthesis of platelet activating factor and eicosanoids, and we will evaluate the therapeutic benefits of the following drugs: platelet activating factor receptor blockage; leukotriene D4 receptor blockage; inhibitor of leukotriene B4 and leukotriene C4 synthesis; inhibitors of thromboxane synthesis and thromboxane receptors. these agents will be administered both acutely and chronically and the beneficial effects assessed through measurements of glomerular function, glomerular morphology and glomerular synthesis of these autacoids. Additionally, we will monitor the in vivo expression of genes controlling the synthesis of fibronectin and collagen. Glomerular mesangial cell cultures from rats and humans will be used in vitro to study the effects of immune stimulation on mesangial synthesis of platelet activating factor, eicosanoids, and matrix proteins including fibronectin and collagens. Immune stimulation will be induced with immune complexes, membrane attack complex, and leukocytes. These experiments will enhance our understanding of mesangial function and biochemistry under conditions which mimic immunologic injury in vivo. We wish to pursue in depth, the effects of platelet activating factor on cultured mesangial cells. These experiments will quantitate and characterize platelet activating factor receptors, G protein linkage of receptors and phospholipases, and intracellular events of signal transduction including phospholipase A2 and phospholipase C-mediated changes. Furthermore, we will test the hypothesis that both positive and negative feedback actions exist mediated through protein kinase C and cyclic AMP-protein kinase A.